Helicobacter pylori infection upregulates interleukin-18 production from gastric epithelial cells.
BACKGROUND
Helicobacter pylori infection induces a biased T helper type 1 (Th1) response that produces IFN-gamma and Fas ligand (FasL). Th1 cytokines are associated with apoptosis in the gastric epithelial cells.


OBJECTIVE
We aimed to define the role of the recently cloned IL-18, a IFN-gamma inducing factor, in gastric mucosal injury induced by H. pylori infection.


METHODS
Twenty-seven gastric ulcer (GU) patients and 20 functional dyspepsia (FD) patients were enrolled in this study. Mucosal biopsy samples were obtained from the gastric antrum and GU site during endoscopy. Samples were used for histological examination, H. pylori culture and in-situ stimulation for 48 h in the presence of 10 microg/ml phytohemagglutinin-P. IL-18, IFN-gamma, and soluble FasL (sFasL) levels in culture supernatants were assayed by the enzyme-linked immunosorbent assay method. IL-18, IL-1beta-converting enzyme (ICE) and caspase-3 were evaluated by western blotting in gastric cancer cell lines (MKN45) cocultured with H. pylori.


RESULTS
All 27 GU patients and ten out of 20 FD patients were found to be H. pylori-positive, whereas ten FD patients were H. pylori-negative. Antral mucosal tissues from H. pylori-positive FD patients contained (P<0.01) higher levels of IL-18, IFN-gamma, and sFasL than those from uninfected FD patients. IL-18, IFN-gamma, and sFasL levels at the ulcer site were significantly (P<0.01) higher than those at distant sites in the antrum. A significant relationship was seen between IL-18 and IFN-gamma levels at the ulcer site (r=0.7, P<0.01). H. pylori eradication led to a significant decrease in the levels of IL-18, IFN-gamma, and sFasL at the ulcer site. Western blotting showed that IL-18, ICE, and caspase-3 were activated in gastric cancer cell lines cocultured with H. pylori.


CONCLUSIONS
This study suggests that H. pylori infection enhanced mucosal injury by stimulating a Th1 response, which was mediated by IL-18 upregulation as well as activation of ICE and caspase-3.
Shimada
Masaaki
M
Department of Gastroenterology, Nagoya University Graduate School of Medicine, Nagoya Memorial Hospital, Showa-ku, Nagoya, Japan.
Ando
Takafumi
T
Peek
Richard M
RM
Watanabe
Osamu
O
Ishiguro
Kazuhiro
K
Maeda
Osamu
O
Ishikawa
Daisuke
D
Hasegawa
Motofusa
M
Ina
Kenji
K
Ohmiya
Naoki
N
Niwa
Yasumasa
Y
Goto
Hidemi
H
D000328:Adult; D000368:Aged; D017209:Apoptosis; D020170:Caspase 1 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D004415:Dyspepsia / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology / Q000382:microbiology; D053222:Fas Ligand Protein / Q000032:analysis; D005260:Female; D005753:Gastric Mucosa / Q000276:immunology* / Q000382:microbiology; D016481:Helicobacter Infections / Q000150:complications / Q000276:immunology*; D016480:Helicobacter pylori / Q000276:immunology / Q000302:isolation & purification*; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis; D020382:Interleukin-18 / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D009924:Organ Culture Techniques; D013276:Stomach Ulcer / Q000276:immunology / Q000382:microbiology*; D015854:Up-Regulation
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D020382:Interleukin-18; D007371:Interferon-gamma; D053148:Caspase 3; D020170:Caspase 1